1. Field of the Invention
This invention relates to novel derivatives of alkyl, phenyl or benzyl 3-oxoandrost-4-ene 17 beta-thiocarboxylates and the corresponding androsta-1,4-dienes. More specifically, it relates to anti-inflammatory 16 alpha,17 alpha-acetonides and 17 alpha-hydroxy-16 alpha-methyl compounds which are substituted at the 6 alpha and 6 beta positions with fluorine substituents. The invention further relates to pharmaceutical anti-inflammatory compositions comprising a selected compound of the invention in combination with pharmaceutically acceptable excipient.
2. Prior Art
Certain 3-oxoandrost-4-ene 17 beta-carboxylic acids which are substituted at the 9 position with chlorine or fluorine and at the 11 position with keto or hydroxy or chloro group are known. See for example U.S. Pat. No. 3,828,080. It is also known that 3-oxoandrost-4-ene 17 beta-carboxylic acids may be substituted at both the 9 alpha and 6 alpha positions with fluoros. See for example U.S. Pat. No. 3,636,010.
It is also known from U.S. Pat. No. 3,989,686 to Phillipps et al of Glaxo that steroids of formula (II) wherein
R.sup.1 is H or CH.sub.3 ; PA1 R.sup.2 is H or CH.sub.3 ; PA1 R.sup.3 is H or, when R.sup.2 is H, C.sub.1-6 alkoxy, C.sub.1-5 alkyl, thiocyanato or halogen; PA1 R.sup.4 is H or CH.sub.3 ; PA1 R.sup.5 is C.sub.1-6 alkyl optionally substituted by halo or NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are the same or different C.sub.1-6 alkyl or R.sup.6 and R.sup.7 together with N are morpholino, thiamorpholine or morpholino substituted with C.sub.1-6 alkyl; and PA1 the dotted line in the "A" ring represent an optional double bond at these positions. These compounds are useful as anesthetics. PA1 X.sup.1 is hydrogen, fluoro, chloro or bromo; PA1 X.sup.2 is .dbd.C.dbd.O or ##STR1## or is ##STR2## when X.sup.1 is chloro; R is alkyl of 1 through 6 carbon atoms or is phenyl or benzyl optionally substituted with a substituent which is alkyl of 1 through 4 carbon atoms, alkoxy of 1 through 4 carbon atoms or halo; PA1 R.sup.1 is hydrogen or alkanoyl of 2 through 6 carbon atoms when R.sup.2 is hydrogen, alpha-methyl or beta-methyl; PA1 OR.sup.1 and R.sup.2 together are 17 alpha,17 alpha-isopropylidenedioxy; and PA1 the bond between C-1 and C-2 is a double or single bond.
Methyl 3 beta-acetoxyallothiolcholonate and methyl 3 beta-acetoxy-etiothiochol-5-enate are also known. See, e.g., Jerger et al, Helv. Chem. Acta. 29, 684-92 (1947).
A heretofore unknown series of 3-oxo-androst-4-ene 17 beta-thiocarboxylates and derivatives thereof being substituted at the 6 alpha and 6 beta positions with fluoro has been discovered and is disclosed herein. The 17 beta-carboxylates exhibit good anti-inflammatory activity and few adverse side effects.